Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.
Cornelis MC., Byrne EM., Esko T., Nalls MA., Ganna A., Paynter N., Monda KL., Amin N., Fischer K., Renstrom F., Ngwa JS., Huikari V., Cavadino A., Nolte IM., Teumer A., Yu K., Marques-Vidal P., Rawal R., Manichaikul A., Wojczynski MK., Vink JM., Zhao JH., Burlutsky G., Lahti J., Mikkilä V., Lemaitre RN., Eriksson J., Musani SK., Tanaka T., Geller F., Luan J., Hui J., Mägi R., Dimitriou M., Garcia ME., Ho W-K., Wright MJ., Rose LM., Magnusson PK., Pedersen NL., Couper D., Oostra BA., Hofman A., Ikram MA., Tiemeier HW., Uitterlinden AG., van Rooij FJ., Barroso I., Johansson I., Xue L., Kaakinen M., Milani L., Power C., Snieder H., Stolk RP., Baumeister SE., Biffar R., Gu F., Bastardot F., Kutalik Z., Jacobs DR., Forouhi NG., Mihailov E., Lind L., Lindgren C., Michaëlsson K., Morris A., Jensen M., Khaw K-T., Luben RN., Wang JJ., Männistö S., Perälä M-M., Kähönen M., Lehtimäki T., Viikari J., Mozaffarian D., Mukamal K., Psaty BM., Döring A., Heath AC., Montgomery GW., Dahmen N., Carithers T., Tucker KL., Ferrucci L., Boyd HA., Melbye M., Treur JL., Mellström D., Hottenga JJ., Prokopenko I., Tönjes A., Deloukas P., Kanoni S., Lorentzon M., Houston DK., Liu Y., Danesh J., Rasheed A., Mason MA., Zonderman AB., Franke L., Kristal BS., Karjalainen J., Reed DR., Westra H-J., Evans MK., Saleheen D., Harris TB., Dedoussis G., Curhan G., Stumvoll M., Beilby J., Pasquale LR., Feenstra B., Bandinelli S., Ordovas JM., Chan AT., Peters U., Ohlsson C., Gieger C., Martin NG., Waldenberger M., Siscovick DS., Raitakari O., Eriksson JG., Mitchell P., Hunter DJ., Kraft P., Rimm EB., Boomsma DI., Borecki IB., Loos RJ., Wareham NJ., Vollenweider P., Caporaso N., Grabe HJ., Neuhouser ML., Wolffenbuttel BH., Hu FB., Hyppönen E., Järvelin M-R., Cupples LA., Franks PW., Ridker PM., van Duijn CM., Heiss G., Metspalu A., North KE., Ingelsson E., Nettleton JA., van Dam RM., Chasman DI.
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.